The ABSITE REVIEW: Practice Questions 2 Edition Steven M. Fiser MD‘The ABSITE Review: Practice Questions 2" Edition Steven M. Fiser MD Hancock Surgical Consultants, LLC Richmond, Virginia ‘This book is not intended for clinical use. Extreme care has been taken to ensure the accuracy of the information contained in this book and to devise the safest and most conservative way of practicing general surgery. However, the authors and publishers are not responsible for errors or omissions in the book itself or from any consequences from application of the information in the book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of this information remains the professional responsibilty of the practitioner. The specific circumstances surrounding any individual patient requires individual diagnosis and treatment. Extreme care has been taken to ensure that the drug dosages herein are accurate, however iliness such as renal failure and other disease states can affect dose. The reader should check the package insert for any drug being prescribed to see the current recommended indications, warnings, and precautions. ‘Some drugs and devices in this text have FDA clearance only for certain indications. Itis the responsibilty of the health care provider to ascertain the FDA status of any drug or device before use ‘The American Board of Surgery inc. does not sponsor nor endorses this book. Allrights reserved. This book is protected by copyright. No part may be reproduced in any means, including photocopying, without the express written consent of the copyright owner The author has never had access to the ABSITE exams used by the American Board of ‘Surgery Inc, other than to take the exam. This book is meant to educate general surgery residents, not reconstruct the ABSITE t © 2015 Hancock Surgical Consultants, LLCre not with The and vever id d isthe any ner, Contents: Cell biology Hematology Blood products Immune System and Wound Healing Transplantation Infection Antibiotics Pharmacology Anesthesia Patient Safety, Outcomes, Ethical-Legal Fluids and Electrolytes Nutrition Oncology Trauma Critical Care Burns Head and Neck Adrenal Gland Thyroid Parathyroid Pituitary Gland Breast Thoracic Cardiac Vascular Gastrointestinal Hormones Esophagus Stomach Liver Biliary System Pancreas Spleen Small Bowel Colon and Rectum Rectum and Anus Hernias and Abdominal Wall Urology Gynecology Neurosurgery Orthopaedics Pediatric Surgery Skin and Soft Tissue Statistics 20 24 36 46 61 70 88 100 140 116 160 182 191 202 208 220 228 230 254 267 273 307 310 325 342 362 395 403 423 459 470 478 489 497 519 531Cell Biology 1 3. 4 5 6 DNA polymerase is involved in a, Transcription b. Transtation c. Duplication 6. Protein carboxylation Answer c. DNA polymerase is responsible for duptication of DNA. DNA polymerase chain reaction uses oligonucleatides to amplify specific DNA sequences (a tool used in research). RNA polymerase is involved in: ‘a. Transcription b. Translation Duplication d. Protein carboxylation ‘Answer c. RNA polymerase is responsible for transcription, the process by which DNA is copied into mRNA. Proteins are synthesized from: a DNA b. rRNA cc tRNA ¢. mRNA Answer d. Ribosomes translate mRNA into specific proteins (amino acid sequences} : ‘Anti-viral protease inhibitors used in patients with HIV work by a. _ Preventing protein precursor cleavage b. Activating lysosomes: : ©. Degrading nbosomes | d. Inhibiting RNA polymerase : Answer a. Protease inhibitors prevent viral replication by selectively binding viral proteases and preventing protein precursor cleavage, which is necessary for the production of infectious viral partick Steroid hormones a, Bind a receptor on the plasma membrane and activate a plasma membrane enzyme b. Bind a cytopiasmic mRNA c, Bind a receptor in the nucleus and affect transcription of RNA 4. Donotenter the cell receptor, enter the nucleus, and affect transcription of Answer b. Steroid hormones bind a receptor in the cell cytoplasm, enter the nucleus as a steroid-receptor complex, and then affect transcription of MRNA for protein synthesis, Thyroid hormone affects transcription after binding a receptor that resides in the nucleus. Steroid and thyroid hormones require 1-2 hours before having effects, Cells divide during what phase of the cell cyci a GI b 6S c G2 aMAnswer d. Cells divide during the M phase (mitosis) Cell cycle - 4 phases G1 - Most variable part, determines cell cycle length Growth factors affect cell during G1 (synthesis) - cell is preparing for division Protein synthesis, DNA replication (DNA polymerase) G2 (G2 checkpoint) ~ stops cell from proceeding into mitosis if there is DNA damage to allow repair (maintains DNA stability) M (mitosis) - cell divides Omeprazole acts by binding: ‘a. He Histamine receptor b HIKATPase c Acetylcholine receptor d.— Gastrin receptor Answer b. Omeprazole blocks the proton pump (H / K ATPase) in parietal cells, 8 Tyrosine kinase: ‘a. Phosphorylates tyrosine residues b. — Decarboxylates tyrosine residues c. Carboxylates tyrosine residues 4d. De-phosphorylates tyrosine residues Answer a. Tyrosine kinase phosphorylates tyrosine residues. imatinib (Gleevec) is @ receptor tyrosine kinase inhibitor used in patients with malignant GIST (gastro-intestinal stromal tumors) 9. What receptor does erythromycin bind to increase gastrointestinal motility? a. Somatostatin receptor b, Acetylcholine and dopaminergic receptors ©. GABA receptor dd. Motilin receptor Answer d. Erythromycin binds the motiin receptor and can be used to increase motility viral the 10. What portion of the lipopolysaccharide complex accounts for its toxicity? a. Lipid A b. Lipid B ©. Lipid C 4. Lipid D of Answer a. Lipid A is the toxic portion of the lipopolysaccharide complex found with gram negative sepsis. Lipid A is the most potent stimulant for TNF- alpha release, 11. Of the following, which is the most critical component in the neovascularization of e ‘tumor metastases? for a HER receptor b. VEGF receptor ¢. Neu receptor d. FGF receptor Answer b. One of the most critical elements in the neovascularization of metastases is the VEGF (vascular endothelial growth factor) receptor. Many new chemotherapeutic strategies target the VEGF receptor (a tyrosine kinase) or VEGF itset. 12. All of the following are true exceptDesmosomes anchor cells to each other Hemidesmosomes anchor cells to platelets Gap junctions allow communication between cells Tight junctions are water impermeable eoge Answer b. Hemidesmosomes anchor cells to extra-cellular matrix. Desmosomes and hemidesmosomes — anchor cells (cell-cell and cell~extracellular matrix molecules, respectively) Tight junctions - occluding junctions that occur between cells; form a water impermeable barrier (eg skin epithelium, bladder epithelium) Gap junctions ~ formed between cells to allow communication 13, _Allof the following are true except a. Keratin is found in hair and nails, b. —Desmin is found in muscle cc. _Vimentin is found in skin d. The above are intermediate filaments Answer c. Vimentin is found in fibroblasts. Intermediate filaments: Keratin (hair and nails) Desmin (muscle tissue) imentin (fibroblasts) 14. Protein kinase A is activated by aa) b. Diacylglycerot cc. cAMP d ADP Answer c. Protein kinase A is activated by CAMP (2 second messenger) Adenylate cyclase forms cAMP from ATP. 15. Protein kinase C is activated by: a Ca b ATP c, cAMP ¢ ADP. Answer a. Protein kinase C is activated by Ca or diacylglycerol (both second messengers). Diacylglyceroi (DAG) and inositol triphosphate (IP) and formed from PIP, by phospholipase C. Ga is released from the mitochondria 16. All of the following are true except 2. Cholesterol increases plasma membrane fluidity b. __Intra-cellular calcium level is very low compared to extra-cellular level cc. — G proteins are GTPases d, The Golgi apparatus is the major site of ATP production Answer d. Mitochondria are the major site of ATP production,nd Hematology Which of the following is the correct order of responses following vascular injury. Vasoconstriction, thrombin generation, platelet adhesion Platelet adhesion, vasoconstriction, thrombin generation Thrombin generation, vasoconstriction, platelet adhesion Platelet adhesion, thrombin generation, vasoconstriction Vasoconstriction, platelet adhesion, thrombin generation enoge Answer e. vasoconstriction, platelet adhesion, thrombin generation Thromboxane: a. Decreases platelet aggregation by increasing release of calcium in platelets b. Decreases platelet aggregation by decreasing release of calcium in platelets ©. Increases platelet aggregation by increasing release of calcium in piatelets d. Increases platelet aggregation by decreasing release of calcium in platelets Answer c. Thromboxane causes platelet aggregation by increasing Ca“ in Platelets. This results in exposure of the Gp Iibillia receptor and platelet binding Prostacyclin a. Decreases platelet aggregation and causes vasodilatation b. Decreases platelet aggregation and causes vasoconstriction c. Increases platelet aggregation and causes vasodilatation d. Increases platelet aggregation and causes vasoconstriction Answer a. Prostacyclin decreases platelet aggregation and causes vasodilatation (mediated through increased cAMP in platelets). All of the following are true except: Prostacyclin is synthesized in endothelium Thromboxane is released from platelets, ASA inhibits cyclooxygenase ‘Thromboxane is regenerated in platelets within 24 hours after ASA Tx Bleeding risk is best assessed with history and physical exam paoce Answer d. Thromboxane is not regenerated in platelets as cyclooxygenase is irreversibly inhibited and platelets do not have nuclear material to re-synthesize cyclooxygenase, Endothelium does contain DNA and can re-synthesize cyclooxygenase Which of the following is required in formation of the pro-thrombin complex Magnesium) Potassium Selenium Cobalamin Calcium eeocm Answer e. Calcium is required in formation of the prothrombin complex. The pro-thrombin complex (Xase complex) uses X, V, calcium, platelet factor 3, and pro-thrombin (Factor I!) Which of the following coagulation factors is not synthesized in the liver: a. Factor V b. Factor VI Factor Vil dé. Factor Vili €. Factor IX24 25. 26. 27 28. 29 Answer d. Factor Vill is synthesized in vasoular endothelium, WF (von Willebrand Factor) is also synthesized in vascular endothelium and is important in hemostasis (links Gplb receptor on platelets to collagen) Which of the following deficiencies results in a normal PT (INR) and prolonged PTT: a. Factor Vil b. Factor V Factor X d. Factor Il Factor Vill Answer e. Factor Vill (8) ‘Which of the following deficiencies results in a prolonged PT (INR) and normal PTT a. Factor VI b. Factor Vil ¢, Factor Vil d. Factor IX e. Factor X Answer b. Factor Vil (7) Which of the following factors has the shortest halt-life Factor Vi Factor Vil Factor Vill Factor IX Factor X Answer b. Factor Vil (7) All of the following are Vit K dependent factors except: a. Factor il b. Factor V c. Factor Vil d. Factor IX e. Factor X Answer b. Factor V All of the following platelet problems are true except a Bernard-Soulier disease involves a Gplb receptor defect b. Glanzmann thrombasthenia involves a Gpllbillia receptor defect c. —_Uremia involves down-regulation of WWF d. Vit K deficiency leads to decreased platelet production ‘Answer d. Vit K deficiency leads to decreased Vit K dependent factor production (li, Vil, IX and X; also protein C and protein S) Al of the following apply to von Willebrand disease except Type Ill disease does not respond to DDAVP (desmopressi Type | and Ill disease have reduced quantity of circulating WWF Type Ill is the MC type itis the MC congenital bleeding disorder The defect is in platelet adhesion paece Answer c. Type lis the most common type of von Willebrand disease All of the following are true for hemophilia A (Factor Vill deficiency) except a. Factor Vill levels should be raised to 100% pre-op before major surgery b. 1" line therapy for hemarthrosis is aspiration of the jointtant ©. Factor Vili levels should be maintained at 80-10% for 14 days post-op after major surgery d. Hemophilia A and hemophilia B have the same bleeding risk which is dependent on factor levels Answer b. 1" line therapy for hemarthrosis is recombinant factor Vill and ice. Range of motion exercises are started well after the bleeding is controlled for hemarthrosis. t line Tx (and often definitive Tx) for any bleeding issues (eg joint, intra- cerebral, contained GI bleed [eg duodenal hematomal) associated with hemophilia A is Factor Vill replacement (for Hemophilia B — Factor IX). Allof the following are true of hemophilia A and B except: a. Patients with severe, life-threatening bleeds and high factor Vill or IX antibody titers should be treated with Factor Vil concentrate b. DDAVP is not effective for Hemophilia B Both have prolonged PT. Both are sex linked recessive Answer ¢. Both hemophilia A and B have prolonged PTT. DDAVP can be used for mild cases of Hemophilia A (stimulates release of Factor Vill / VWF) All the following are true of antiphospholipid antibody syndrome (APAS) except a. Classically has an elevated PTT (from lupus anticoagulant antibodies) that is not corrected with FFP (hypercoaguable with elevated PTT) Is associated with elevated anti-cardiolipin antibodies Patients are prone to spontaneous abortions Cardiolipin is a cell membrane phospholipid 's associated with elevated anti-lupus anticoagulant antibodies pees Answer d, Cardiolipin is a mitochondrial membrane phospholipid All of the following are true of hypercoaguable states except a, Antithrombin Ill deficiency is associated with heparin resistance b. The mutation for Factor V Leiden is on protein C c. The MC acquired hypercoaguiabilty disorder is smoking d. _ Hyperhomocysteinemia treatment is with folate and cyanocobalamin Answer b. Resistance to activated protein C (Factor V Leiden) is caused by a mutation on Factor V. itis the MC congenital hypercoagulability disorder. The primary mechanism of uremia induced coagulopathy is: a. Preventing conversion of fibrinogen to fibrin b. Down regulation of the Gplb receptor Inhibition of von Willebrand factor (VWF) release d. Down regulation of the Gp libilia receptor e, Inhibition of Antithrombin Ill Answer c. Uremia causes inhibition of vWF release and is the key dysfunctional element in uremic coagulopathy A.50 yo man on chronic hemodialysis is scheduled to undergo open inguinal hemia Fepair. Which of the following is the best therapy to help prevent intra-op bleeding a. Hemodialysis b. Platelets c. DDAVP d. Factor Vil concentrate Answer a. For non-acute situations, hemodialysis the day prior to surgery is the best preventative therapy for avoiding uremia and intra-op bleeding.36. 36. A 60 yo man on chronic hemodialysis presents with a clotted AV fistula graft and encephalopathy (BUN 125). You emergently place a temporary dialysis line which continues to bleed around the site. The best initial treatment for this patient is: a. Hemodialysis, b. Platelets c. DDAVP d. Factor Vil concentrate Answer c. The best acute treatment for bleeding associated with uremia is DDAVP (which causes release of WWF [and Factor Vill] from endothelium). If that fails, platelets should be given Prior to aortic valve replacement, you are unable to get the patient's activated clotting time (ACT) and PTT to an appropriate range that is safe for cardio-pulmonary bypass despite several rounds of heparin (ACT and PTT are normal). ‘The patient was on heparin prior to surgery. The most appropriate next step is: ‘Abandon surgery DDAVP Anti-thrombin It Factor Vill concentrate Cryoprecipitate ‘Answer c. Pre-operative heparin therapy can decrease anti-thrombin Ill levels and cause relative anti-thrombin Ill deficiency resulting in heparin resistance. ‘Txis recombinant anti-thrombin Ill, If not available, FFP should be given (has highest concentration of AT-iI}) Ant-thrombin Ill deficiency can also present as fresh red thrombus foliowing heparin administration for vascular procedures (eg fresh thrombus in an aortic graft after finishing the proximal anastomosis and moving the cross clamp) After placing a left ventricular assist device (LVAD), diffuse bleeding occurs. Fibrinogen level is 20. The most appropriate next step is a FFP b. DDAVP c. — Cryoprecipitate d. Factor Vii concentrate fe. Recombinant WWF:VIIl Answer c. Cryoprecipitate has the highest concentration of fibrinogen Normal fibrinogen levels should be > 100. Cryoprecipitate contains high concentrations of Factor Vill, vWF, and fibrinogen ‘The best treatment for thrombolytic overdose (eg urokinase, tissue plasminogen activator (tPAl) is ‘a. Aminocaproic acid (Amicar) b. FFP. c. Packed red blood cells d. Cryoprecipitate Answer a. Thrombolytics work by converting plasminogen into plasmin. Plasmin then degrades fibrin, Aminocaproic acid (Amicar) works by binding plasminogen and preventing the conversion of plasminogen to plasmin Fibrinogen levels < 100 are associated with increased risk and severity of bleeding. Tx with aminocaproic acid is indicatedng Is ce. as gen 10 38. 40. at 42, 43, Prostatectomy or TURP can release urokinase, causing fibrinolysis and bleeding issues (eg persistent hematuria); Tx — aminocaproic acid (Amicar) Which of the following would indicate disseminated intravascular coagulation (DIC), as ‘opposed to simple fibrinolysis: Elevated D-dimer b. Elevated fibrin split products Decreased fibrinogen d. Decreased platelet count Answer d. Fibrinolysis is not associated with a decreased platelet count. DIC results in an elevated PT and PTT, decreased platelets, and decreased fibrinogen, ‘4.50 yo man is admitted for sigmoid diverticulitis (on CT scan). Despite fluid resuscitation and antibiotics he has the following lab values: BP 90/60, HR 105, WBC. 20, PTT 100, platelets 36, INR 2.3, fibrinogen 40, elevated D-dimer, and elevated fibrinogen split products. The most essential step to improve this patient condition is a. Rule out pulmonary embolism b, Colonoscopy c. FFP, cryoprecipitate, and platelets d, Sigmoidectomy Answer d. This patient has DIC based on lab values. Although blood products should be given pre-op, they will likely be soon consumed by the DIC process. ‘The most important issue here is to remove the DIC source (ie sigmoidectomy for diverticulitis) All of the following are true of deep venous thrombosis (DVT) except The MC source of pulmonary embolism (PE) is lio-femoral DVT The left leg develops DVT 2x more commonly than the right IVC filters should be placed above the renal veins ‘An infected indwelling catheter with tip thrombosis requires removal ‘An upper extremity DVT (eg arm swelling) related to an indwelling catheter is treated with catheter removal and heparin eaece ‘Answer c. IVC filters should be placed below the renal veins. If placed above renal veins, an embolus that clogs the filter can result in renal failure. HD catheters with infected thrombosis can't be salvaged (require removal). All of the following are true of DVT risk except a. The risk is elevated in pregnant patients compared to non-pregnant patients, b. The risk is elevated in patients undergoing surgery for malignancy compared to those without malignancy ©. The risk is elevated in patients undergoing open gastric bypass compared to those undergoing laparoscopic gastric bypass d. The risk is elevated in patients with Leiden Factor @, The best therapy for prevention of post-thrombotic syndrome is early thrombolytics Answer c. DVT risk is the same for patients undergoing open gastric bypass ‘compared to laparoscopic gastric bypass. The pneumoperitoneum created intre- op (increasing risk of DVT) for patient undergoing laparoscopy is equally Weighted by decreased ambulation post-op (increasing risk of DVT) in patients undergoing open surgery. Most adult surgery in-patients should receive DVT prophylaxis. ‘A 25 yo woman develops severe left leg pain and swelling to the level of her buttock. Her leg is massively swollen on exam with a blue appearance. Duplex U/S shows an44, 48. 46 iliofemoral DVT. She still has motor and sensation in the extremity. The most appropriate next step is: Open thrombectomy Heparin only Catheter directed thrombolytics INC filter Answer c. This patient has phlegmasia cerulea dolens. This can result in leg gangrene so therapy is indicated. Catheter directed thrombolytics are superior to just heparin therapy alone for this condition, Your patient has a recurrent pulmonary embolism despite appropriate anticoagulation and you decide to place an IVC filter. Pre-procedure U/S shows a lio-caval DVT, the majority of which goes down the left common iliac vein. The most appropriate next step is ‘2. Access the left femoral vein b. Access the right femoral vein ¢. Access the right internal jugular vein 4. Access the left internal jugular vein Answer c. Patients with iliocaval DVT who require IVC filters should have them placed using the intemal jugular vein as access (the right internal jugular vein is easier than the left for IVC filter placement). You start Coumiadin on a patient with @ pulmonary embolus. Three days later, he starts sloughing off skin across his arms and legs. All of the following are true of this patients most likely condition except a. Thisis prevented by starting heparin before Coumadin b. Patients with protein C deficiency are more susceptible c. The skin sloughing is caused by skin necrosis d. This patient most likely has hemophilia A Answer d. Warfarin induced skin necrosis occurs when Coumadin is started without being on heparin 1%. It results from a relative hypercoaguable state because of the shorter half-life of protein C and S compared to factors Il, Vil, IX and X (Vit K dependent factors), Protein C and S decrease after Coumadin before the other factors decrease, resulting in a hypercoaguable state. Patients with protein C deficiency are at increased risk for warfarin induced skin necrosis. It is prevented by starting heparin before giving Coumadin. Al of the following are true except a. — Low molecular weight heparin (LMVVH) binds Anti-thrombin Ill (AT-Ill) and neutralizes Factors lla and X LMWH is not reversed with protamine Fondaparinux is a direct thrombin inhibitor Argatroban works independently of AT-IIh Dabigatran (Pradaxa, a direct thrombin inhibitor) requires dose adjustment for renal insufficiency Answer a. LMWH (eg Lovenox) binds AT-III and inhibits Factor Xa only. Unfractionated heparin binds AT-IIl and inhibits Factors lla and Xa A 50 yo woman receiving heparin suffers a small stroke. Her platelet count is 88 (baseline platelet count at admission was 225). Her PTT is 85. Which of the following is most accurate for diagnosing HIT in this patient: a. IgG to heparin b. Current platelet count of 88 c PTT 85 4d, Admission platelet count of 225,Answer a. Antibodies to heparin (most commonly IgG to heparin-PF4 complex) is the most accurate way of diagnosing HITT. 48, Which of the following is the best choice for continued anticoagulation in the above patient a. Continued IV heparin with steroids b. Subcutaneous heparin leg ¢. Low molecular weight heparin (Lovenox) d. Argatroban ‘Answer d. Direct thrombin inhibitors (eg Argatroban, Bivalirudin [Angiomax]) are on the treatment of choice for suspected HITT. re Argatroban is preferred for patients with renal insufficienoy (has hepatic metabolism) and bivalirudin is preferred for patients with liver problems (has renal metabolism) 49, A 80 yo manis diagnosed with stage Il colon CA. He had a drug-eluting coronary artery stent placed 1 month ago and is on clopidogrel (Plavix). The most appropriate next step is vem a Surgery while on Plavix b. Hold the Plavix only and operate after 5-7 days ©. Hold the Plavix, start a short-acting Iib/ilia inhibitor, and operate in 5-7 days d. Hold the Plavix and only start the Hlb/iiia inhibitor if stent thrombosis occurs s ‘Answer c. Holding Plavix, starting a short-acting IIbiliia inhibitor, and operating in 8-7 days is appropriate. Abruptly stopping Plavix within the first year of drug- eluting stent placement is associated with stent thrombosis and acute myocardial infarction. BLEEDING RISK = History and Physical Exam - best way to predict bleeding risk od = Normal circumcision - does not ruie out bleeding disorders; can stil have clotting factors from mother (eg hemophilia A - factor Vill crosses placenta) x = Abnormal bleeding with tooth extraction or tonsillectomy - picks up 99% of patients with a bleeding disorder = MCC of surgical bleeding - incomplete hemostasis = Warfarin, Plavix, and ASA - hold for 5-7 days prior to major surgery skin NORMAL COAGULATION / ANTI-COAGULATION = Initial response to vascular injury (in order) ~ vasoconstriction, platelet adhesion, and thrombin generation d = Coagulation Factors *¢ _Allare synthesized in the liver except Factor Vill (synthesized in endothelium) © WWF (cofactor for Vill) - also synthesized in endothelium * Exposed collagen, prekallikrein, kininogen and Factor XII initiate the intrinsic pathway nt * Tissue factor and Factor VI initiate in the extrinsic pathway * Vit dependent cofactors - Il, Vil, IX and X; also protein C and protein S ‘Warfarin inhibits these factors * Factor Vil - has shortest half-life = Prothrombin complex (Xase complex) * Includes Factor X, Factor V, calcium, platelet factor 3, and prothrombin * Prothrombin complex forms on platelets; catalyzes formation of thrombin 9 = Thrombin (Key to coagulation cascade) * Converts fibrinogen to fibrin (and fibrinogen degradation products) * Activates factors V and Vill * Activates platelets © Generated on platelet surtace (prothrombin complex above) * _ Fibrin + platelets = platelet plug (hemostasis) = VWF - links Gplb on piatelets to collagenFibrin - cross-links platelets by binding Gpiibiilla Anti-thrombin Ill (AT-IIl, Key to anticoagulation) © Binds and inhibits Factors tla (thrombin), IX, X, and X1 © Heparin binds AT-Il and increases activity (1000 x) Protein C - degrades Factors V and VIII, also degrades fibrinogen Protein $ - protein C cofactor MC congenital hypercoaguable disorder - resistance to activated protein C (Leiden Factor V) MC acquired hypercoaguable disorder - smoking Key RFs for venous thrombosis (Virchow’s triad) - stasis. endothelial injury, and hypercoagulability Key RF for arterial thrombosis - endothelial injury COAGULATION FACTORS Fresh frozen plasma (FFP) - contains all coagulation factors ‘Corrects coagulopathy from liver disease or warfarin (high PT or INR) Is frozen so it takes time to thaw; effects are immediate after infusion Cryoprecipitate ¢ Has highest levels of Factor Vill, vWF, and fibrinogen © Good for patients with tow fibrinogen (= 100) © Can be used for vWD and Hemophilia A Vitamin K (IV, IM, or oral) - IV requires 12 hours for effect; used for warfarin reversal may be hard to re-anticoagulate with wartarin after receiving Vit K Prothrombin complex concentrate (factors Il, VIl, IX and X) - prepared from human FFP; given as an injection (is not frozen) | Preferred Tx to acutely reverse warfarin for bleeding (eg intra-cranial hemormhage, major GI bleeding) ‘Do not have to wait for thawing and has highest concentration of Vit K dependent co-factors (warfarin inhibits these) If prothrombin complex not available, give FFP and IV Vit K © _Aiso for patients on warfarin undergoing emergency surgery DDAVP - causes release of VIll and vWF from endothelium © Used for acute reversal of uremic coagulopathy © Can be used for von Willebrand disease (Types / and 1, not Type II!) COAGULATION MEASUREMENTS PT (pro-thrombin time; INR) - used to follow warfarin Tx © Best test for fiver synthetic function ¢ Picks up Factors # (fibrinogen), lt (prothrombin), V, Vil, and X PTT (partial thromboplastin time) - used to follow heparin Tx (want PTT 60-90 sec) © Picks up all factors except Factor Vil and Factor Xill © __ Can be used to follow argatroban and bivalirudin ACT (activated clotting time) - want ACT 150-200 for routine anticoagulation Want act > 480 for cardiopulmonary bypass INR >1.5 - relative contraindication to performing surgical procedures INR >1.3 - relative contraindication to central line placement, percutaneous needle biopsies, and eye surgery CONGENITAL BLEEDING DISORDERS von Willebrand disease (von Willebrand factor [WWF] problems) © MC congenital bleeding disorder (AD) MC Sx: epistaxis: others - gum bleeding, heavy menstrual flow, ecchymosis VWF production occurs in endothelium VWF links Gplb receptor on platelets to collagen Dx: PT normal, PTT normal or slightly prolonged Positive ristocetin test; measurement of VWF protein levels, platelet function analyzer (PFA-100), prolonged bleeding time (rarely used) Tx recombinant factor Vill:vWF (best Tx); DDAVP (except Type Ill); cryoprecipitate (highest vWF concentration of all blood products)rsal man ved) © Type! (MC type, 70%) - reduced quantity of WWF (mild Sx’s) © Type ll- have enough vWF but doesn’t work well © Type ll- almost no WF, get severe bleeding (““DDAVP does not work) Hemophilia A (factor Vill deficiency, sex linked recessive) * MC Sx: hemarthrosis; others - muscle, Gl tract, or brain hemorrhage © Factor Vill crosses placenta > newborns may not bieed at circumcision Spontaneous bleed - occurs at levels < 1% ¢ Dx: prolonged PTT and a normal PT ¢ Tx recombinant Factor Vill (best Tx) or eryoprecipitate (highest Factor Vill concentration of all blood products) Elective surgery - need Factor Vill levels 100% pre-op Need to keep levels at 80-100% for 14 days after surgery Monitor PTT every 8-12 hours ¢ —_Hemarthrosis (bleeding in joint spaces) > **do not aspirate ‘Tx recombinant Factor VIll, ice, and late range of motion exercises (well after the bleeding is controlled) * Epistaxis, intracerebral hemorrhage, contained GI hemorrhage (subcapsular liver/splenic hematoma; duodenal hematoma), retroperitoneal hematoma, or hematuria - Tx: recombinant Factor Vili * Development of alloantibodies can occur with both recombinant and plasma derived factor Vill or factor IX (Tx for severe, life-threatening bleeding in patients with high Factor Vill or IX antibody titers - recombinant factor Vil [7]) Hemophilia B (factor IX deficiency, sex linked recessive) - Sx's same as above © Dx: prolonged PTT and normal PT © Tx recombinant factor IX (best Tx) or FFP © Want peri-op levels similar Hemophilia A * _ Txfor severe, life-threatening bleeding in patients with high Factor IX antibody titers - recombinant factor VII Platelet defect bleeding disorders * Bernard-Soulier syndrome (Gplb receptor detect) * Glanzmann thromboasthenia (Gplibiilia receptor defect) © Dx: platelet function analyzer (PFA-100), platelets aggregation studies. prolonged bleeding time © Tx platelets UREMIC COAGULOPATHY Occurs in patients on dialysis (BUN > 60-80); have bleeding problems Uremia inhibits release of vWF (key problem) Tx hemodialysis (best Tx: reverses uremia and coagulopathy) * Hemodialysis the day before a procedure is usual Acute reversal Tx (eg bleeding patient) > give DDAVP (stimulates endothelial felease of factor Vill and vWF; 30 minute time of onset, lasts 4 hours); give platelets if refractory DIC (Disseminated Intravascular Coagulopathy) Consumption of blood products that results in bleeding MCC - sepsis (eg pneumonia, cholecystitis, diverticulitis) Dx: low platelets, low fibrinogen, high fibrin split products, high o-dimer * Prolonged PT and prolonged PTT Tx: need to correct the underlying cause (eg antibiotics for sepsis or removal of septic source) CONGENITAL HYPERCOAGULABILITY DISORDERS Present as arterial or venous thrombosis / emboli (eg cold leg, PE, stroke) Factor V Leiden Mutation (resistance to activated protein C) * MC congenital hypercoagulability disorder (5% of population) © Mutation is on Factor V Hyperhomocysteinemia (MTHFR mutation or folate, B6 or B12 deficiency) * __ Hyperhomocysteinemia > Tx: folate, pyridoxine, cyanocobalamin Prothrombin gene mutation (G20210A) Protein C deficiencyProtein S deficiency Anti-thrombin Il deficiency * Causes heparin resistance (heparin will not increase PTT) © Have to give recombinant AT-III 1" (or FFP), then heparin © FFP has highest concentration of AT-IIl of all blood products © __ Can develop after previous heparin exposure ‘Tx for all above except AT Ill deficiency and hyperhomocysteinemia > post-op heparin, then warfarin WARFARIN-INDUCED SKIN NECROSIS Occurs when placed on Coumadin without being heparinized first Skin sloughs off extremities Due to short half-life of proteins C and $ which are decreased before pro- coagulation factors; get hypercoaguable state > thrombosis) Patients with protein C deficiency are especially susceptible Tx: heparin if it ocours; prevent by starting heparin before warfarin HITT (Heparin-induced thrombocytopenia and thrombosis) Anti-heparin antibodies cause platelet destruction and at times activation with thrombosis. IgG binds to heparin after formation of the heparin-piatelet factor 4 complex Forms a white clot; can occur with just one low dose of heparin Clinical suspicion 4) platelet drop to < 100 or < 50% baseline or: 2) arterial or venous thrombosis / embolism (cold leg, DVT, PE) Dx: antibodies to heparin * ELISA (quickest to get) ‘* _ Serotonin Release Assay (SRA; most specific but have to send out) Tx: stop heparin and start direct thrombin inhibitor if the patient requires. anticoagulation (eg Argatroban, Bivalirudin), then warfarin Platelet transfusion is contraindicated with HITT - causes thrombosis Argatroban is a direct thrombin inhibitor and not dependent on AT-Il APAS (Anti-Phospholipid Antibody Syndrome) ‘Sx's: thrombosis (venous or arterial) and/or loss of pregnancy Dx: high anti-cardiolipin or lupus anticoagulant antibodies Cardiotipin is a mitochondrial phospholipid Lupus anticoagulant antibodies - prolong coagulation reactions © Patients have hypercoagulability with elevated PTT (that does not correct with FFP) Causes - primary or from autoimmune disease (eg SLE) ‘Tx: heparin, then warfarin after surgery (lifelong) DEEP VENOUS THROMBOSIS (DVT) Post-op DVT prevention - majority of adult surgery inpatients should receive LMWH prophylaxis unless contraindicated (in addition to early ambulation + sequential compression devices [SCD’s)) * SCDs - improve venous return but also induce fibrinolysis with compression (release of tPA) ‘© Trauma patients with highest risk of DVT - spinal cord injury Post-op DVT Tx - LMWH (preferred over unfractionated heparin - therapeutic levels achieved quicker, stabilizes clot, prevents extension), then direct thrombin inhibitor (preferred eg Pradaxa, Xarelto) ot warfarin Sx's: 50% are asymptomatic; pain, swelling, warmth, unexplained fever © MC DVT location - calf © MC location to result in PE - llio-femoral * Left leg 2x MC than right (left iliac vein compressed by right iliac artery) Virchow’s triad - venous stasis, hypercoagulability, endothelial wall injury Dx: US 16vith 16 Phlegmasia alba dolens (painful, swollen white leg) - less severe than below Phlegmasia cerulea dolens (painful, swollen blue leg) - more severe: can lead to gangrene; usually occurs with iliofemoral DVT © Tx catheter-directed thrombolytics Emergent open balloon or percutaneous mechanical (eg AngioJet) thrombectomy if extremity threatened (ie loss of sensation or motor function) * 50% of these patients have a malignancy somewhere Post-thrombotic syndrome - pain, heaviness, edema, ulcers Long term Cx in patients with DVT * __ Prevented with use of catheter-directed thrombolytics for early DVT DVT and pregnancy - warfarin contraindicated in pregnancy (teratogenic; Tx: LMWH) * Increased risk related to pressure on veins in pelvis / lower extremities and circulating hormones DVT and gastric bypass surgery © The higher the BMI, the gréater the risk of DVT ‘* No difference between laparoscopic and open procedures © Prevention - LMWH prophylaxis and early ambulation © __ PEs the MCC of death after gastric bypass (50% of post-op deaths) ‘Temporary IVC filters (inferior vena cava; can be removed) © Indications: PE with contraindications to anticoagulation Documented PE while on anticoagulation Recent pulmonary embolectomy Free-floating IVC, ilio-femoral, or deep femoral DVT (controversial indication) Want to place IVC fier befow renal veins PE with IVC filter in place - embolus comes from ovarian (gonadal) veins, IVC Superior to filter, or SVC (superior vena cava; upper extremities) * Free floating ilio-femoral DVT and need to place IVC filter - enter the internal jugular vein, pass through the SVC and right atrium down to the IVC; place fitter below renal veins Hemodialysis catheter (or an indwelling catheter) ‘© Tip thrombosis - Tx: systemic heparin or PA down catheter If infected with thrombosis - Tx: remove catheter © Upper extremity DVT (ie arm swelling, Dx: duplex U/S) related to catheter - Tx remove catheter, start heparin (then Coumadin) CLOPIDOGREL (Plavix) | platelet ADP receptor inhibitor (prevents platelet cross-linking) Have a prolonged bleeding time Issues with coronary stents - high risk of stent thrombosis (and myocardial infarction) if Plavix is stopped early after stent placement Elective surgery recommendations: ‘* Bare metal stents - Plavix for 6 weeks before elective surgery © Drug eluting sients - Plavix for 4 year before elective surgery = Emergency surgery - operate on Plavix, have platelets available = Semi-urgent surgery - stop Plavix 5-7 days pre-op (takes this long to clear); bridge with short-acting lIb/lila inhibitors [eg eptifibatide (Integrilin)] = Tx or bleeding associated with Plavix: platelets HEPARIN Unfractionated Heparin (UFH) © Binds AT-IIl and inhibits Factors lla and Xa Want PTT 60-90; 1/2 life is 60-90 minutes Cleared by reticuloendothelial system (macrophages, spleen) Indications - massive PE; bridge to oral therapy for various conditions Can use in pregnancy (does not cross placental barrier; warfarin does) Pre-op - hold heparin for 6 hours prior to surgery Re-start heparin after 48 hours if not bleeding Side effects: early - HITT, long term use - osteoporosis, alopecia© Acute reversal Tx: protamine (binds and reverses heparin) MC S/E — protamine reaction (1%): an anaphylactic reaction with hypotension and bradycardia (Tx: fluid resuscitation, epinephrine) = — Low molecular weight heparin (LMWH) and Fondaparinux Indications - DVT and sub-massive PE (initial Tx); DVT prophylaxis Do not need to monitor PTT LMWH is a selective AT-IIl - Xa inhibitor Fondaparinux is a direct thrombin inhibitor LMWH has much smaller HITT risk compared to UFH Fondaparinux has no HITT risk These are.not reversed with protamine (non-reversible agents) DVT prophylaxis dose is higher in post-op gastric bypass patients compared to other post-op patients © Need dose adjust ment for renal insufficiency DIRECT THROMBIN INHIBITORS (Vit K antagonists) = Intravenous - Argatroban, Bivalirudin (AngioMax) * Indications - HITT requiring continued anticoagulation, percutaneous coronary interventions, Not reversible Argatroban has hepatic metabolism Bivalirudin has renal metabolism Follow PTT for both (want PTT 60-90) ral - dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis) Indications - DVT, PE, atrial fibrillation (not from heart vaive problem) ‘Not reversible; hold Xarelto/Eliquis 24-48 hours before surgery: Pradaxa 3-5 days Need dose adjustment for renal insufficiency Do not need to follow INR Oral direct thrombin inhibitors compared to Coumadin have the same efficacy with less bleeding x’s . ee eer oeeee WARFARIN (Coumadin; Vit K antagonist) = Indications - mechanical valves, attial fibrillation due to heart valve problem = Acute reversal Tx (eg head or moderate to severe GI bleed): prothrombin complex * Ifnotavailable, give FFP and IV Vit K = Side-effects - bleeding ox’s THROMBOLYTICS (eg tissue Plasminogen Activator [tPA], streptokinase) = Indications - usually for vessel thrombosis and ischemia © Given with heparin, usually for 8 - 24 hours (avoid giving > 48 hours — significant bleeding risk) * Thrombolyties work by converting plasminogen into plasmin © Plasmin then degrades Factors V and Vill, fibrinogen and fibrin = Follow fibrinogen levels > fibrinogen < 100 has a high bleeding risk and Tx with aminocaproic acid is indicated = Thrombolytic overdose (fibrinogen < 100) - Tx: aminocaproic acid (Amicar; is an anti-ibrinolytic) = Prostate surgery - can release urokinase, activates plasminogen > thrombolysis; ‘Tx aminocaproic a = Absolute contraindications to thrombolytics: Active or recent internal bleeding or known bleeding disorder © Intracranial pathology (stroke, significant brain trauma, or neurosurgery within last 3 months; brain tumor) * Aortic dissection = Major contraindications to thrombolytics: ‘© Recent (< 10 days) surgery, organ biopsy, eye surgery, obstetric delivery, or major trauma ‘+ Left heart thrombus, active peptic ulcer, or uncontrolled severe HTN * Pregnancy tPA (ti PROS THROlays vant ‘in 18 tPA (tissue Plasminogen Activator) Released from endothelium Induces fibrinolysis by converting plasminogen to plasmin Plasmin - degrades Factors V and Vill along with fibrinogen and fibrin ‘* Lose platelet plug, get elevated fibrin degradation (split) products (FDPs or FSPs, eg D-dimer) Alpha-2 antiplasmin - natural inhibitor of plasmin, released from endothelium Prostate surgery (eg TURP, prostatectomy) can release urokinase; induces fibrinolysis (converts plasminogen to plasmin) © Sx's: bleeding © Tx aminocaproic acid (inhibits plasmin) PROSTACYCLIN (PGI) Released from endothelium Inhibits platelet aggregation and causes vasodilation . = increases CAMP in platelets ASA irreversibly binds cyclooxygenase, but cyclooxygenase is re-synthesized in endothelium (has nuclear material unlike platelets) - result is normal PGI, production and platelet inhibition THROMBOXANE (TXA,) Released from platelets Causes platelet aggregation and vasoconstriction Increases calcium in platelets > exposes Gpllbillla and Gplb receptors (induces platelet binding) ASA irreversibly binds cyclooxygenase, decreasing TXA production for the life of the platelet (7 days, platelets do not have nuclear material — can't re-synthesize cyclooxygenase) - result is decreased TXA, production and decreased platelet, aggregation ASA - prolongs bleeding time WBCs - contain nuclear material; RBCs - no nuclear material; platelets - no nuclear materialBlood Products 50. A.21 yo female patient with blood type B requires PRBCs. Which of the following is the safest blood type to give her: Type A, Rh negative ‘Type AB blood, Rh negative Type O blood, Rh negative Type A, Rh negative ‘Type B, Rh positive peoce Answer c. Type O blood (universal donor) contains no A or B antigens. Rh negative blood is indicated for females of pre-pubescent or of child-bearing age. 51. _Allof the following are true of acute hemolytic transfusion reactions except Bilirubin is likely low b. — Haptoglobin is likely low c. Free hemoglobin is likely high d. Volume resuscitation is the 1 step in management €. tis antibody mediated Answer a. Bilirubin would be elevated due to RBC hemolysis. 52. All the following are true of transfusion related acute lung injury (TRALI) except ‘a. _ Is caused by donor antibodies which bind recipient WBCs which then lodge in tung b. Txis similar to ARDS Result in decreased capillary permeability d. Results in pulmonary edema Answer c. TRALI results in increased capillary permeability (and fluid leakage) and is caused by donor antibodies to recipient WBCs. 53. Prevention of febrile non-hemolytic transfusion reaction involves: 2. Heating blood to destroy the wiite blood cells b. Prophylactic antibiotics ! c. NSAID's 4. Leukocyte fitter Answer d. Febrile non-hemolytic transfusion reaction is caused by white blood cells in donor blood and can be prevented by using a leukocyte filter during transfusion (the filter size is large enough to allow red blood cells through but small enough to trap white blood cells) 54. One week after RBC transfusion, your patient develops diffuse purpura and epistaxis. Her platelet count is 12 (starting platelet count 250). Which of the following is correct a. Emergent platelet transfusion is indicated b. Thisiis likely due to bacterial contamination c. Thisis likely a bone marrow problem 4d. Platelet alloimmunization likely occurred with a previous transfusion Answer d. Platelet alloimmunization likely occurred with a previous transfusion. This patient has post-transfusion purpura, in which the patient developed antibodies to platelets (trom previous transfusion [platelets, or RBC / FFP contaminated with a few platelets] or pregnancies). Subsequent transfusion (platelets or RBCs / FFP with platelet contamination) activates the reaction Important to note that the reaction is against all platelets, including the patient's own platelets. ‘De immunoglobulin (primary Tx), plasmapheresis, no further platelet transfusions 20 55. 4 BLOO ‘ e a t et i mal ef at aC55. All of the following are true of blood products except a The MCC of infectious related mortality following blood transfusion is sthe hepatitis B ‘The MC blood product containing bacterial contamination is platelets ‘The MC bacterial contaminant is skin flora (eg staph epidermidis) Blood transfusion increases the risk of infection The MCC of transfusion related death is TRAL! eaoo ‘Answer a. The MCC of infectious related mortality following blood transfusion is bacterial contamination. The MC blood product to contain a bacterial 1 contaminant is platelets because they are stored at room temperature (good age medium for bacterial growth). TRALI recently replaced ABO incompatibility as the leading cause to transfusion related death. BLOOD TRANSFUSION = Type O blood (universal donor) - contains no A or B antigens, © Males can receive Rh positive blood © Females who are pre-pubescent or of child-bearing age should recaive Rh negative blood = Type AB blood (universal recipient) - contains both A and B antigens; can only be used in an AB blood type patient = Type specific blood request - assesses ABO compatibility: but not minor antigens = Type and screen - looks for preformed antibodies to minor HLA antigens odge = Type and crossmatch - same as type and screen and the blood bank will crossmatch the number of units requested = MCC mortality from transfusion - TRALI (previously clerical error leading to ABO incompatibility) = Packed red blood cells (pRBCs) © 1 unit of pRBCs - should increase Hgb by 1 gmidl (Hct by 3 ae) * PRBCs are stored in citrate (CDPA) for preservation - citrate binds Ca” Citrate causes hypocalcemia with massive blood transfusion (> 10 units/24 hours or > 6 units within 3 hours) © Stored pRBCs last 3 weeks * Storage effects on pRBCs - V 2.3 DPG, W pH, 4K’, and * lactic acid * Trying to raise Hgb without giving blood (eg Jehovah's Witness with low Het before surgery) > Tx: Epoetin and Fe supplementation Should raise hemoglobin 1-2 gnvdl after a week (Hct 3-5 after a week) * Iron deficient anemia (microcytic anemia) in male or post-menopausal female ® Need to screen for colon CA or another GI source of bleeding © CMV negative pRBCs (from CMV negative donors) - used for CMV sero- agh negative pregnancy, organ and bone marrow TXP candidates/recipients, HIV patients, and low birth weight infants = Platelets “s. © Platelet transfusion indications: 2t 1) < 10,000 (very high risk of spontaneous bleeding) 2) < 20,000 with infection or bieeding risk (eg post-op patients) 3) < 60,000 with active bleeding or pre-procedure © Contraindications ~ TTP, HUS, HELLP, HITT (may need to give platelets to control severe bleeding with these syndromes) * 1 six pack of platelets (1 unit) - should increase platelet count by 50,000 ion. = Fresh frozen plasma (FFP) * Contains all coagulation factors (includes protein C, protein §, and AT-II}) * Good for patients with deficiency of coagulation factors (eg dilutional coagulopathy with massive transfusion, DIC [controversial], liver disease, patients on warfarin, PT > 17 pre-procedure) ts © Can be used for Hemophilia B = Cryoprecipitate © Has highest levels of Factor Vill, vWF, and fibrinogen * Good for patients with low fibrinogen (< 100; consider aminocaproic acid 1") © Gan be used for WWD and Hemophilia A 20INFECTIOUS COMPLICATIONS FROM TRANSFUSION Hep B - 1: 200,000, Hep C - 1: 2,000,009, HIV - 1: 2,000,000 Blood is also tested for syphilis, HTLV, and West Nile virus MC contaminant (of all viruses and bacteria) - skin flora (eg staph epidermidis) others - yersinia, pseudomonas, E. coli MCC of infectious-related death - bacterial contamination (not viral) MC blood product with bacterial contaminant - platelets (1:50,000) BLOO * Platelets are stored at room temp - good medium for bacteria growth ‘* Platelets last for 5 days at room temp * Not refrigerated because half-life would be decreased * _ Sx’s of transfusion associated bacteremia (within 90 minutes of transfusion) ~ fever (> 39 C), shivering, tachycardia (> 120); Tx: broad spectrum antibiotics All blood products carry risk of HIV and hepatitis except albumin and immunoglobulins (these are heat treated) Immune system - blood product transfusion alters the immune system, placing . patients at increased risk of infection MASSIVE BLOOD TRANSFUSION EFFECTS Dilution of coagulation factors and platelets - causes coagulopathy Hypocalcemia - manifested as hypotension and coagulopathy A ‘© Calcium is required for clotting cascade ‘* Citrate - used in stored blood; binds calcium; causes hypocalcemia Hypothermia (cold body temp) - causes coagulopathy (slows enzyme reactions) ‘* Use blood warmer to help prevent : © Best Tx for patient hypothermia - warm air conduction (Bair Hugger) BLOOD TRANSFUSION REACTIONS - HEMOLYSIS ‘Acute hemolytic transfusion reaction - caused by ABO incompatibility © Sx'si chills, rigors, fever, back pain, hematuria, tachycardia, shock In anesthetized patients, can present as diffuse bleeding and hypotension Can lead to renal failure, DIC, and shock Caused by preformed recipient antibodies against donor RBC ABO antigens Is a Type Il Hypersensitivity Reaction Dx Low haptoglobin (< 50 mg/dL; binds Hgb, then gets degraded) High free hemoglobin (> 5 g/dL) High unconjugated bilirubin High lactate dehydrogenase (LDH) © Tx stop transfusion: fluids and pressors (maintain urine output): HCO; Delayed hemolytic transfusion reaction - from minor antigens © Sx's: mild jaundice; may go unnoticed (5-10 days after transfusion) © Caused by preformed recipient antibodies against donor RBC minor HLA antigens ¢ Tx observe if stable; type + screen (checks for HLA antigens) with future transfusions Alloimmunity ‘+ Body gains immunity against antigens of foreign blood products 1% risk of developing alloimmunity with RBC transfusion 25% risk of developing alloimmunity with platelet transfusion Alloimmunity can develop against RBCs or platelets Alloimmunization against RBCs - can cause delayed hemolytic transfusion reaction (see above); generally well tolerated © Alloimmunization against platelets can resutt in: 1) Refractoriness to platelet transfusion (ie platelet count didn't rise as much as it should have after platelet transfusion) 2) Post-transfusion purpura (rare) - antibodies to platelets develops (from previous transfusions (platelet, or RBC / FFP contaminated with a few platelets] or pregnancies). Subsequent transfusion (platelets or RBCs / FFP with platelet contamination) activates the reaction. {s a life- threatening problem as the patient's antibodies tum against the patient's own platelets (not just the transfused ones). Severe thrombocytopenian= 9 ens. n nas can occur (platelet count < 18), usually about a week after transfusion. This is more common in women (RF - multiple previous pregnancies) Tx immunoglobulin (primary Tx). plasmapheresis, no further platelet transfusions = Non-immune hemolysis - from squeezing the blood bag BLOOD TRANSFUSION REACTIONS - OTHER = Febrile non-hemolytic transfusion reaction * SX's: fevers and rigors 0-6 hours after transfusion Caused by preformed recipient antibodies against donor WBCs Causes cytokine release Tx. stop transfusion; acetaminophen Use WBC (leukocyte) filters for subsequent transfusions (WC filters are generally used for all transfusions) = Urticaria (rash) © Reaction of recipient antibodies to plasma proteins in the blood product, * MCC - IgA deficient patient (with preformed IgE antibodies to IgA) receiving IgA blood; other allergens (consumed by the donor) - nuts, penicilin * __Tx histamine blockers (diphenhydramine [Benadryl}), supportive » Anaphylaxis (rare) - urticaria, bronchospasm, hypotension, angioedema * Same mechanism as urticaria above * Can be an airway emergency © Tx epinephrine (Epi pen), fluids, steroids, histamine blockers = Transfusion-related acute lung injury (TRALI) © Sx's: hypoxia, diffuse alveolar infiltrates, fever Non-cardiogenic pulmonary edema < 6 hours after transfusion Donor antibodies bind recipient WBCs which then lodge in the lung WBCs release mediators causing 7 capillary permeability Results in non-cardiogenic pulmonary edema < 6 hours after transfusion Tx: similar to ARDS (may require intubation)Immune System and Wound Healin 56. The key growth factor in wound healing is: pth 63. All bd. PAF c EGF a FGF Answer a. PDGF is the key growth factor in wound healing 57. _Allof the following participate in angiogenesis except al a PDGF b PAF Hypoxia d FGF Answer b. PAF does not have angiogenesis properties. Hypoxia is the most Potent stimulus for angiogenesis. 58. _Allof the following are chemotactic for inflammatory cells except a ILe b LTB 65. All © Ca and C3a 4. TGF-beta Answer d. TGF-beta is not chemotactic for inflammatory cells. It is generally considered immunosuppressive 59. _Allof the following are functions of the listed cytokine except, a. IL-6 increases hepatic acute phase proteins b. IL-8 induces PMN chemotaxis and angiogenesis ©. IL-0 upregulates the inflammatory response 66. Alic d. — ILinduces fever Answer c. IL-10 down-regulates the inflammatory response. 60. _Alllof the following hepatic proteins are increased during the acute phase response except a. Albumin b. C reactive protein & 63 4. Fibrinogen 67. Allo ‘Answer a. There is decreased synthesis of albumin, pre-albumin, and transferrin during the acute phase response. 61, Which of the following Infections is associated with defects in cell mediated immunity a Staph b E.Coli Tuberculosis 4. Proteus ‘Answer c. Infections associated with defects in cell mediated immunity 68. Allo! include intra-cellular pathogens (eg TB, other mycobacterium, viruses) 62, _Allof the following are true of cell adhesion molecules except a. Selectins are involved in rolling adhesion b. L-selectin binds E-selectin and P-selectin . _ ICAM binds beta-2 integrin (CD 11/18) molecules d. P-selectin is located on leukocytesAnswer d. P-selectin is located on platelets 63. All of the following are true of complement except: a C8b, C8b, C7, C&b and Cab form the membrane attack complex b, C1, C2, and C4 are found only in the classic pathway © Ct and C2 are anaphylatoxins 4. Factors B, D, and P (properdin) are found only in alternate pathway Answer c. C3a, C4a and CSa are anaphylatoxins. 64. Allof the following are true of oxygen radicals except a. The primary injuring mechanism of oxygen radicals is DNA damage b. Cellular defense against superoxide anion primarily involves superoxide dismutase ©. Cellular defense against hydrogen peroxide primarily involves taurine 4. Chronic granulomatous disease is caused by decreased superoxide radical (2) formation due to a defect in the NADPH-oxidase enzyme system Answer c. Cellular defense against hydrogen peroxide primarily involves peroxidase and catalase, 65. All of the following are true except: a LTC,, LTD, and LTE, (slow-reacting substances of anaphylaxis) cause bronchoconstriction and vasoconstriction, followed by increased permeability (wheal and flare) b. Thyroid hormone has a major role in inflammation and injury c. Dense granules have adenosine (as ATP, ADP), serotonin, calcium d. LTB, is chemotactic for PMNs and eosinophils Answer b. Thyroid hormone does not have a major role in inflammation. 66. _Allof the following are true except: a The most predominate cell in the 1" 24 hrs of a wound is PMNs b. The most predominant cell at days 3-4 after a wound is macrophages c, The order of cell arrival in wound is macrophages, platelets, PMNs, {ymphocytes, and fibroblasts d. The most predominate cell type in a7 day old wound is fibroblasts ‘Answer c. The order of cell arrival in wound is platelets, PMNs, macrophages, lymphocytes, and fibroblasts. 87. Allof the following are true except a, The most predominant type of collagen in the body is Type | b, The most predominant type of collagen being synthesized in a healing wound in the 1° 24 hours is Type Il ¢. The maximum collagen amount in a wound occurs at 3 weeks ty: 4. Maximum tensile strength of a wound occurs at 3 weeks Answer d. Maximum tensile strength occurs at 8 weeks. Although the ‘maximum collagen amount occurs at 3 weeks, remodeling and cross-linking Occur to increase tensile strength, which is maximum at 8 weeks. 88. All of the following are true except ‘The most important cell involved in wound healing is macrophages The most predominant collagen type in cartilage is Type Il Vit prevents the negative effects of steroids on wound healing Keloids are confined to the original scar area The best method for inhibiting keloid formation is steroid injection following keloid excision paoge Answer d. Keloids are not confined to original scar (hypertrophic scar tissue is)69. Peripheral nerves regenerate at: a. 0.01 mm/day b. 0.1 mmiday ct mm/day da. 5 mmiday Answer c. Nerves regenerate at 1 mmiday. 70. The most important factor in the healing of wounds by secondary intention is: a. Tensile strength of the wound b. Epithelial integrity cc. Platelet activating factor d. Prostacyclin Answer b. The most important factor in wound healing by secondary intention is epithelial integrity. 71. The most important factor in the healing of wounds by primary intention is: a. Tensile strength of the wound b. Epithelial integrity c. Platelet activating factor d.— Prostacyciin Answer a. Wound healing by primary intention is dependent on the tensile strength of the wound. This is created by collagen cross-linking. Sutures hold the wound together until appropriate collagen deposition and cross-linking occurs. 72. A21 yo man presents to the ED twelve hours after sustaining a large gluteal laceration. Other than dirt, you do not see any pus or signs of infection. Which of the following is most appropriate: Primary closure with suture No closure and let the wound granulate in on its own Delayed closure 78 Primary closure with staples ‘Wound vac only oaoge Answer c. Do pot close wounds that are > 6 hours old (perform wound debridement, leave open, then close 48 hours later [delayed primary closure]), 73. Which of the following best prevents wound infection following an open wound injury: a. Prophylactic IV antibiotics INFL. b. Topical antibiotics 2 c. Chlorhexidine skin preparation d. Wound vac . Wound debridement Answer e. Wound debridement 74, A patient with a large open gluteal laceration wound injury returns to clinic and the ‘wound is much smaller. This is primarily a result of: a. Lymphocytes b. Macrophages . PMNs 4. Myofibroblasts = Answer d. Myofibroblasts participate in wound contraction 75. Allof the following are true except: . 26tion ile hold f the e). ury 26 a. Natural killer are involved in T’ cell receptor and antigen-MHC class recognition b. _Newbomn’s innate immunity has poor phagocyte chemotaxis (eg PMNs, macrophages), making them susceptible to cutaneous infections c. IL-2 is released from helper T cells and activates cytotoxic T and natural killer cells 4. Cytotoxic T cells (CD8) attack non-self antigens attached to MHC class | receptors Answer a. Natural killer cells are not involved in antigen-MHC class recognition, They attack cells with low expression of MHC (missing self) and cells with bound antibody. ‘Anewbomn’s innate immunity has poor phagocyte chemotaxis (PMNs and macrophages), making them susceptible to cutaneous infections (make sure you wash your hands), 78. Cachexia in patients with cancer is primarily the result of a Le b Ls e IL-0 4. TNF-alpha Answer d. TNF-alpha promotes cachexia in patients with cancer. 77. Which is the primary antibody found in secretions from the gut: a igk b. gG IgM d IgD e IgE Answer a. IgA is the primary antibody found in gut secretions. 78. Which of the following is most effective in helping prevent osteoporosis: a VitC b. Vitk c Vita a vit Answer D. Vit D INFLAMMATION = Injury - leads to exposed collagen as well as platelet-activatina factor (PAF) and tissue factor release from endothelium = Platelets bind collagen - release growth factors (eg platelet-derived growth factor PDGF); leads to PMIN and macrophage recruitment = Macrophages - have the dominant role in inflammation and wound healing © Main producer of growth factors (PDGF) and cytokines (TNF-alpha and IL-1) which attract other inflammatory cells and fibroblasts, * Involved in phagocytosis and remove debris (monocytes become macrophages) * Involved in both cell-mediated and antibody-mediated immunity (have Fe receptor for antibodies) = Order of cell arrival in wound - Platelets, PMNs, Macrophages, Lymphocytes, Fibroblasts = Predominant cell type by day: © Days 0-2 PMNS © Days 3-4 Macrophages * Days § and on Fibroblasts Wound healing stages © Inflammation (PDGF, PAF) - 1" step in normal wound healing© Proliferation (PDGF, FGF, EGF) © Remodeling Cell mediated immunity © Involves macrophages, cytotoxic T cells, and natural killer cells © Does not involve antibodies © Intradermal skin test (eg PPD for tuberculosis) - tests cell-mediated immunity * Infections associated with defects in cell mediated immunity - intra-cellular pathogens (eg TB, other mycobacterium, viruses) Other cell types ‘© Mast cells - main cell type involved in Type | hypersensitivity reactions © Basophils - Type | Hypersensitivity reactions * Eosinophils - parasitic infections, Type | hypersensitivity reactions Innate immune system includes inflammation and complement CYTOKINES Main cytokines released with inflammation - TNF-alpha (#1) and IL-1 + Vast majority of cytokines are produced by macrophages TNF-alpha (tumor necrosis factor-alpha) © Main source - macrophages © 4scell adhesion molecules (eg ICAM, selectins); is procoagulant © Activates PMNs and other macrophages > leads to growth factor production > cell recruitment © AHR, * cardiac output, Y SVRI > high concentration can cause myocardial depression, circulatory collapse, and MSOF * Causes cachexia in patients with CA * Main source - macrophages Effects similar to TNF and synergizes TNF ‘+ Induces fever (is PGE, mediated in hypothalamus) Raises thermal set point, causing fever NSAIDs - / fever by reducing PGE. synthesis, * Alveolar macrophages - cause fever with atelectasis by releasing IL-1 IL-6 - hepatic acute phase proteins (see below) IL-8 - PMN chemotaxis (+ other infiammatory cells) and angiogenesis IL-10 - down regulation inflammatory response ( TNF-alpha, IL-2, IL3, and interferons; down-regulates antigen presenting cells [APCs}) Interferons - released by lymphocytes in response to viral infection; activate inflammatory cells, inhibit viral replication, upregulate MHC GROWTH FACTORS PDGF (platelet-derived growth factor) - Key factor in wound healing © Chemotactic for and activates inflammatory cells Chemotactic for and activates fibroblasts Angiogenesis and epithelialization Chemotactic for smooth muscle cells. Accelerates wound healing "AF (piatelet-activating factor) Activates platelets; PAF is a phospholipid Chemotactic and activates inflammatory cells +s adhesion molecule expression * __ Notstored, generated by phospholipase in endothelium, other cells, FGF (fibroblast growth factor) - chemotactic and activates fibroblasts, angiogenesis, epithelialization EGF (epidermal growth factor) - chemotactic and activates fibroblasts, angiogenesis, epithelialization TGF-beta (transforming growth factor-beta) - primarily immunosuppressive (inhibits lymphocytes and leukocytes) Chemotactic factors * For inflammatory cells - PDGF, PAF, IL-6, LTB-4, C5a and C3a © Forfioroblasts - PDGF, FGF, EGF see veces 28 HEnity lular stion ial sis, asis, its = Angiogenesis factors - hypoxia (#1), PDGF, FGF, EGF, IL-8. ‘* Produced by macrophages and platelets in response to hypoxia * Hypoxiais the most potent stimulus for angiogenesis * PAF does not have angiogenesis properties = Epithelialization factors - PDGF, FGF, EGF = PMNs - last 2 days in tissue (last 7 days in blood) a Platelets - last 7 days HEPATIC ACUTE PHASE PROTEINS Proteins that are increased or decreased in response to inflammation = IL-6 - most potent stimulus = Increased synthesis - C-reactive protein (an opsonin, activates complement), amyloid Aand P, fibrinogen, haptoglobin, ceruloplasmin, alpha-t antitrypsin, and C3 (complement) = Decreased synthesis - albumin, prealbumin, and transferrin CELL ADHESION MOLECULES = Selectins - involved in rolling adhesion (1" step in transmigration process); L- selectin (on leukocytes) binds to E-selectin (endothelial) and P- selectin (platelets) = Beta-2 integrins (CD 11/18 molecules) * Found on leukocytes and platelets * Involved in anchoring adhesion and transendothelial migration «Bind ICAM, VCAM, etc = ICAM, VCAM, PECAM, and ELAM * Found on endothelial cells © Involved in anchoring adhesion and transendothelial migration © Bind beta-2 integrin molecules (above) COMPLEMENT = Classic pathway © Activation mechanisms: 1) Antigen-antibody complex (IgG or IgM only) or: 2) Direct binding of pathogen to C1 © Initia! step is formation of C1 complex (2 C1 molecules) * Factors C1, C2, and C4 - found only in the classic pathway = Alternative pathway ‘+ Activation mechanisms - endotoxin, bacteria, other stimuli Initial step is C3 activation *_ _ Factors B, D, and P (properdin) - found only in alternative pathway = C3 activation - common to and convergence point for both pathways Mg” required for both pathways = Products: + Anaphylatoxins - C3a, C4a, and C5a;‘P vascular permeability; bronchoconstriction; activate mast cells and basophils © Cell membrane attack complex: C5b-C9b (CSbC6bC7bC8bCAb) Inserted into pathogen cell membrane, makes hole cell lysis Can also attack normal cells infected with bacteria © Opsonization - C3b and C4b; enhances phagocytosis of antigen Chemotaxis of inflammatory cells (PMNs, macrophage) - Ca and C5a OXYGEN RADICALS = Oxidants generated in inflammation (oxidants and producers) * Superoxide anion radical (O:) NADPH oxidase * Hydrogen peroxide (H202) Xanthine oxidase, NADPH oxidase = Cellular defenses against oxidative species (oxidants and defense) © Superoxide anion radical ‘Superoxide dismutase (need Cu + Zn) Converts to hydrogen peroxide * Hydrogen peroxide Glutathione peroxidase, catalase = Primary injuring mechanism of oxygen radicals - DNA damage = Respiratory burst (macrophages, PMNs) - releases superoxide anion and hydrogen peroxide: used to attack bacteria directly and cells infected with bacteria 20= Chronic granulomatous disease © Defect in NADPH-oxidase enzyme system in PMNs and macrophages © Results in decreased superoxide radical (O°) formation PLATELET GRANULES = Alpha granules © Aggregation Factors - platelet factor 4, vWF, fibrinogen, fibronectin ‘© Beta-thromboglobulin - binds thrombin © PDGF and TGF-beta © Factors V and Xill = Dense granules (ASC) - Adenosine (as ATP or ADP), Serotonin, Calcium LIPID MEDIATORS = Mainly involved in infiammation regulation = Initial substrate is phospholipid essential fatty acids (in cell membrane) © Phospholipids > (phospholipase) > Arachadonic a © Glucocorticoids inhibit phospholipase and production of everything below = — Cyclooxygenase (COX) pathway (produces prostaglandins) © PGi: (prostacyclin) and PGE, ‘Systemic and pulmonary vasodilation (W SVR, Y PVR) ¥ platelet aggregation Bronchodilation © TXAz (thromboxane), PGG,, PGH:, Systemic and pulmonary vasoconstriction (4? SVR, * PVR) * platelet aggregation * ASA inhibits cyclooxygenase = Lipoxygenase pathway (produces leukotrienes and lipoxins) © Are leukocyte derived molecules © Leukotrienes LTC, LTD, LTE, slow-reacting substances of anaphylaxis Bronchoconstriction Vasoconstriction followed by “* permeability (wheal and flare) LTB, - chemotaxis of PMNs and eosinophils © Lipoxins - anti-inflammatory (W chemotaxis, W transmigration) es (neural response to injury) - peak 24-48 hrs after injury ® Neuroendocrine response to injury © Afferent nerves from site of injury stimulate ACTH, ADH, growth hormone, epinephrine, and norepinephrine release = Thyroid hormone ~ does not play a major role in injury WOUND HEALING = Wound healing phases: 1) inflammation, 2) Proliferation, and 3) Maturation and Remodeling = Inflammation (1-10 d, see previous section) = Proliferation (5 days to 3 weeks) © Granulation tissue [ = vascularized extracellular matrix (ECM)] Provisional ECM - hyaluronic acid (primary component, is @ glycosaminoalycan); produced by fibroblasts: undergoes neovascularization (endothelial cells) © Epithelialization (1-2 mm/day, requires granulation tissue) Keratinocytes (epithelial cells) from hair follicles (#7 source), wound edges, and sweat glands migrate across granulation tissue © Wound contraction by myofibroblasts (peaks at 10-15 days) © Collagen deposition by fibroblasts; provides wound strength ‘Type I collagen predominant collagen in wound (although Type Ml is predominant type synthesized in 1" 48 hours) = — Maturation and Remodeling (3 weeks to 1 year) © Maximum collagen synthesis occurs at 3 weeks > net amount then does not. change although production and degradation occurs 30